Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis

ABSTRACT

Pharmaceutical compositions are described that contain one agent for treatment of sinusitis and a surfactant. The compositions are prepared to have a surface tension that renders the composition effective for treatment of sinusitis.

RELATED APPLICATIONS

This application is a continuation of allowed U.S. application Ser. No.10/231,804 filed Aug. 28, 2002, which is a continuation of U.S.application Ser. No. 09/577,623, filed May 25, 2000 to Osbakken et al.,now U.S. Pat. No. 6,576,224. This application claims priority under 35U.S.C. § 119(e) to each of U.S. provisional application Ser. Nos.60/142,618, 60/142,620, 60/142,621, 60/142,622, 60/142,624, 60/142,741,and 60/142,881, each filed on Jul. 6, 1999, and to each of U.S.provisional application Ser. Nos. 60/194,078, 60/193,509, 60/193,508,60/193,507 and 60/193,510, each filed Apr. 3, 2000. The disclosure ofeach of the above-referenced utility and provisional applications isincorporated herein by reference in its entirety.

FIELD

The present invention relates to pharmaceutical compositions comprisingone or more active ingredients selected from the group consisting ofanti-infective, anti-inflammatory and mucolytic agents, and particularlyto compositions formulated as a solution in a unit dose or multi-dosevials for aerosol administration to treat chronic sinusitis.

BACKGROUND

There are a number of air-filled cavities called sinuses in the skull(Stedman's Medical Dictionary, 27th Edition, page 1644, (1999),Lippincott Williams & Wilkins, Baltimore, Md.). Four pairs of sinusesknown as the paranasal sinuses, connect the space (known as the nasalpassage) running from the nostrils and up through the nose. These fourpairs of paranasal sinuses are the frontal sinuses, the maxillarysinuses, the ethmoid sinuses, and the sphenoid sinuses. They arelocated, respectively, in the forehead, behind the cheekbones, betweenthe eyes, and behind the eyes. A membrane lining the sinuses secretesmucus, which drains into the nasal passage from a small channel in eachsinus. Healthy sinuses are sterile and contain no bacteria. In contrast,the nasal passage, normally contains many bacteria that enter throughthe nostrils as a person breathes.

A number of factors and/or processes are involved in maintaining healthysinuses. The mucus secreted by the membrane lining must be fluid butsticky, in order to flow freely yet absorb pollutants and entrapbacteria. It must also contain sufficient amounts of bacteria-fightingsubstances, such as antibodies. Additionally, small hair-likeprojections called cilia, located in the nostril, must beat in unison topropel mucus outward, in order to expel bacteria and other particles.Moreover, the mucous membranes themselves must be intact, and the sinuspassages must be open to allow drainage and the circulation of airthrough the nasal passage. When one or more of these processes orfactors are amiss, causing obstruction of the sinus passage, aninfection called sinusitis develops.

Sinusitis is an inflammation of the membrane lining one or moreparanasal sinuses. There are three different types of sinusitis: acute,recurrent acute, and chronic. Acute sinusitis is characterized aslasting less than three weeks or occurring less than four times a year.Acute sinusitis can be successfully treated using antibiotics, leavingno damage to the linings of the sinus tissue. Recurrent acute sinusitisoccurs more often but leaves no significant damage. Chronic sinusitislasts longer than three weeks and often continues for months. In casesof chronic sinusitis, there is usually tissue damage. According to theCenter for Disease Control (CDC), thirty seven million cases of chronicsinusitis are reported annually.

Causes of Sinusitis

The most common cause for sinusitis is a viral cold or flu that infectsthe upper respiratory tract and causes obstruction. Obstruction createsan environment that is hospitable for bacteria, the primary cause ofacute sinusitis (Etkins et al., 1999 Nidus Information Services, Inc.Well-Connected Report: Sinusitis. June 1999. (Online)www.well-connected.com.). The bacteria most commonly found in acutesinusitis are Streptococcus pneumoniae (also called pneumococcalpneumonia or pneumococci), H. influenzae (a common bacteria associatedwith many respiratory infections in young children), and Moraxella (orBranhamella) catarrhalis. Less common bacterial culprits include otherstreptococcal strains including Staphylococcus aureus.

Fungi are an uncommon cause of sinusitis, but its incidence isincreasing. The fungus Aspergillus is the common cause of fungalsinusitis. Others include Curvularia, Bipolaris, Exserohilum, andMucormycosis. Fungal infections can be very serious and should besuspected in people with sinusitis who also have diabetes, leukemia,AIDS, or other conditions that impair the immune systems. Fungalinfections can also occur in patients with healthy immune systems. Therehave been a few reports of fungal sinusitis caused by Metarrhiziumanisopliae which is used in biological insect control.

Chronic or recurrent acute sinusitis can be a lifelong condition and mayresult from untreated acute sinusitis that causes damage to the mucousmembranes, medical disorders that cause chronic thickened stagnantmucus, or abnormalities in the nasal passage such as polyps, enlargedadenoids, cleft palate, or tumors. The same organisms that cause acutesinusitis are often present in chronic sinusitis. In addition, about 20%of chronic sinusitis cases (Etkins et al., 1999, Id.) are caused byStaphylococcus aureus (commonly called Staph infection). Along withthese bacteria, certain anaerobic bacteria, particularly the speciesPeptostreptococcus, Fusobacterium, and Prevotella, are found in 88% ofcultures in chronic sinusitis cases (Etkins et al., 1999, Id.). Fungican also cause chronic and recurrent sinusitis. An uncommon form ofchronic and highly recurrent sinusitis is caused by an allergic reactionto fungi, usually, aspergillus, growing in the sinus cavities. Fungalsinusitis usually occurs in younger people with healthy immune systemsand is more likely to be found in warm climates.

Symptoms of Sinusitis

In acute sinusitis, symptoms almost always present are nasal congestionand discharge which is typically thick and contains pus that isyellowish to yellow-green. Severe headache occurs, and there is pain inthe face. A persistent cough occurs particularly during the day. Otherupper respiratory symptoms and fever may be present. Sneezing, sorethroat, muscle aches, and fatigue are rarely caused by sinusitis itself,but may result from symptoms or causes, such as muscle aches caused byfever, sore throat caused by post-nasal drip, and sneezing resultingfrom allergies.

The symptoms of recurrent acute and chronic sinusitis tend to be vagueand generalized, last longer than eight weeks, and occur throughout theyear, even during nonallergy seasons. Nasal congestion and obstructionare common. Yellowish discharge, chronic cough, bad breath, andpostnasal drip may occur. Sufferers do not usually experience facialpain unless the infection is in the frontal sinuses, which results in adull, constant ache. However, facial tenderness or pressure may bepresent.

Site-specific symptoms depend on the location of the infection. Frontalsinusitis causes pain across the lower forehead. Maxillary sinusitiscauses pain over the cheeks and may travel to the teeth, and the hardpalate in the mouth sometimes becomes swollen. Ethmoid sinusitis causespain behind the eyes and sometimes redness and tenderness in the areaacross the top of the nose. Sphenoid sinusitis rarely occurs by itself.When it does, the pain may be experienced behind the eyes, across theforehead, or in the face. Rare complications of sinusitis can produceadditional symptoms which may be severe or even life threatening.

Treatments of Sinusitis

The primary objectives for treatment of sinusitis are reduction ofswelling, eradication of infection, draining of the sinuses, andensuring that the sinuses remain open. Less than half of patientsreporting symptoms of sinusitis need aggressive treatment and can becured using home remedies and decongestants alone. Steam inhalation andwarm compresses applied over the sinus are often sufficient to relievediscomfort. Many over-the-counter decongestants are available, either intablet form or as sprays, drops, or vapors, which bring the medicationinto direct contact with nasal tissue.

Antibiotics are prescribed if decongestants fail to relieve symptoms orif other problems exist, including signs of infection (such as yellowishnasal discharge). They prevent complications, relieve symptoms, andreduce the risk of chronic sinusitis. Most patients with sinusitiscaused by bacteria can be successfully treated with antibiotics usedalong with a nasal or oral decongestant.

Chronic sinusitis is often difficult to treat successfully, however, assome symptoms persist even after prolonged courses of antibiotics. Theusefulness of antibiotics in treating chronic sinusitis is debated.Steroid nasal sprays are commonly used to treat inflammation in chronicsinusitis. For patients with severe chronic sinusitis, a doctor mayprescribe steroids, such as prednisone. Since oral steroids can haveserious side effects, they are prescribed only when other medicationshave not been effective.

When medical treatment fails, surgery may be the only alternative intreating chronic sinusitis. Studies suggest that the most patients whoundergo surgery have fewer symptoms and better life. Presently, the mostcommon surgery done is functional endoscopic sinus surgery, in which thediseased and thickened tissues from the sinuses are removed to allowdrainage. This type of surgery is less invasive than conventional sinussurgery, and serious complications are rare.

Considerations and Concerns of Treatments

Sprays, drops, and vapors work quickly but often require frequentadministration. Nasal decongestants may dry out the affected areas anddamage tissues. With prolonged use, nasal decongestants becomeineffective. The tendency is to then increase the frequency of use to asoften as once an hour. Withdrawal from the drugs after three to fivedays of over-frequent use can itself cause symptoms of sinusitis and thereturn of nasal congestion phenomenon known as rebound effect.Short-acting nasal decongestants may cause rebound effect after onlyeight hours. Rebound effect leads to dependency when the patient takesthe decongestant to treat the rebound effect, the drug becomesineffective, the patient withdraws, and the condition rebounds again,with the nasal passages becoming swollen and burning. Eventually, thecondition can become worse than before the medication was taken. Nasaldecongestants are generally recommended for no more than one to threedays of use because of this risk.

Some oral decongestants may cause constriction of other vessels in thebody, temporarily raising blood pressure in people with hypertension.Other side effects of oral decongestants include insomnia, agitation,abnormal heart rhythms (particularly in people with existing cardiacproblems), and urinary retention in men with enlarged prostates.Decongestant sprays and drops, too, are absorbed into the body and cansometimes cause these side effects.

The most common side effect for nearly all antibiotics isgastrointestinal distress. Antibiotics also double the risk for vaginalinfections in women. Certain drugs, including some over-the-countermedications, interact with antibiotics, and all antibiotics carry therisk for allergic reactions, which can be serious in some cases. Thus,patients should inform their physician of all medications they aretaking and of any drug allergies.

Oral antibiotics are usually prescribed for 7 to 10 days. Patients musttake all of the tablets prescribed; failure to do so may increase therisk for reinfection and also for development of antibiotic-resistantbacteria. It should be noted, however, that even after antibiotictreatments, between 10% and 25% of patients still complain of symptoms.

Of major concern to physicians and the public is the emergence ofbacterial strains that have become resistant to common antibiotics dueto frequent exposure. It should be noted that the average person is notyet endangered by this problem. The risk is greatest in hospitals andnursing homes, but it is still not high. Nonetheless, the prevalence ofsuch antibiotic-resistant bacteria has increased dramatically worldwide,and caution should be exercised.

Nebulization Therapy

Nebulization is a conventional treatment for pulmonary infectionsrelated to cystic fibrosis, because it is relatively easy and safe touse, and because it delivers antibiotics topically to the site ofinfection, with little systemic absorption of the antibiotics.Nebulization has also been known to have been used for sinus infectionsand pulmonary infections, related to bronchiectasis. Thus, there are fewsystemic side effects.

Small Aerosolized Particles for Treating Sinusitis

Yokota et al., Japanese Journal of Antibiotics 609(15):48 (1995) reportsadministration of cefmenoxime using a nebulizer to treat sinusitispatients. These authors evaluated cefmenoxime against clinical isolatesfrom sinusitis patients, and found that minimum inhibitoryconcentrations were lower when a one percent (1%) solution was used witha nebulizer. The paper speculates that sufficient concentrationsexceeding such minimum inhibitory concentrations would be obtained bynebulizer treatment using a cefmenoxime nasal solution.

Guevara et al., Anales O.R.L. Iber.-Amer. XVIII, 3:231-238 (1991),describes aerosol therapy for treating patients suffering from chronicsinusitis. The disclosed aerosol therapy involves delivery of atherapeutic composition comprising 500 mg of Cefotaxime, 5 mgmethylprednisolone, and 1.5 ml N-acetylcysteine using an air-jetnebulizer for 15-20 minutes, every 8 hours, over a total period of 15days. The air-jet nebulizer produces aerodynamic particle diameters ofaverage mass of four microns. Guevara et al. reports a success rate of96%. However, Guevara et al. does not disclose adding a surfactant toassist deposition, penetration, and retention of the antibiotic in thesinuses. It is also noted that the aerosol therapy of Guevara et al.requires frequent treatments over a long period of time.

Kondo et al., Acta Otolaryngol. Suppl. 525:64-67 (1996), reportstreatment of paranasal sinusitis using fosfomycin (FOM) aerosol. Kondoet al. describes delivery of 4 ml of 3% FOM solution using either ajet-type nebulizer or a ultrasonic nebulizer. The jet-type nebulizerproduces aerosol particles having about 0.5 to 0.7 μm in diameter, whilethe ultrasonic-type nebulizer produces particles having about 2-4 μm indiameter. The results of Kondo et al. indicate that the ultrasonic-typenebulizer delivers a higher concentration of FOM to the maxillary sinussurface and is therefore more effective in treating paranasal sinusitisthan the jet-type nebulizer. Although Kondo et al. suggests that thepreferred aerosol particle size is about 2-4 μm in diameter fordeposition of a higher level of antibiotic in the maxillary sinus, Kondoet al. does not disclose an administration schedule or the addition of asurfactant to the FOM solution to further increase the deposition of FOMin the sinuses.

Small Aerosolized Particles for Pulmonary Treatment

Smith et al., U.S. Pat. No. 5,508,269, discloses the use ofaminoglycoside aerosol formulations to treat patients suffering fromendobronchial infection. Smith et al. describes delivery of theaminoglycoside formulation using a jet or ultrasonic nebulizer thatproduces aerosol particle size between 1 and 5 μm. The formulationcomprises 200 to 400 mg of aminoglycoside dissolved in about 5 ml ofsolution containing 0.225% sodium chloride and it has a pH between 5.5to 6.5. Although Smith teaches delivery of aminoglycoside to theendobronchial space using a nebulizer for the treatment endobronchialinfection, Smith does not teach an aerosol formulation for treatment ofsinusitis and does not disclose a treatment schedule. It is also notedthat the aerosol particle size disclosed in Smith et al. is a broadrange. It is not predictable what fraction of the aerosol particlesbetween 1 to 5 μm will deposit in the sinuses, and what fraction of theaerosol particles will have a diameter of 1 μm, 2 μm, etc.

Rubin et al., U.S. Pat. No. 5,925,334, describes the use of aerosolizedsurfactant to promote pulmonary airway clearance. The method of Rubin etal. comprises administering a formulation containing a surfactant usinga PARI LC Jet nebulizer for 15 minutes, 3 times a day for 14 consecutivedays, to patients suffering from bronchitis or cystic fibrosis. However,Rubin does not teach the use of aerosolized antibiotic or aerosolizedantibiotic and surfactant combination to treat sinusitis.

Schmitt et al., U.S. Pat. No. 4,950,477, teaches a method of preventingand treating pulmonary infection by fungi using aerosolized polyenes.The method comprises administering to a patient suffering from pulmonaryinfection by Asperigillus about 0.01 mg/kg to 6.0 mg/kg of a polyene inan aerosol of particles having an aerodynamic diameter between about 0.5μm to about 8 μm. Schmitt et al. specifically discloses theadministration of amphotericin B. Although Schmitt et al. teachesaerosolized polyenes for treatment of pulmonary infection, Schmitt etal. does not provide guidance for using aerosolized polyenes fortreating sinusitis.

O'Riordan et al., Journal of Aerosol Medicine, 20(I):13-23 (1997),reports the effect of nebulizer configuration on delivery of aerosolizedtobramycin to the lung. O'Riordan et al. discloses the delivery oftobramycin using either an ultrasonic nebulizer delivering aerosolparticles having between 1.45 to 4.3 μm or a jet nebulizer deliveringaerosol particles having between 1.25 μm. The results of O'Riordan etal. show that nebulizer configuration affects both the amount ofaerosolized tobramycin inhaled as well as the particle size.Specifically, nebulizers that produce large particles are prone toconsiderable deposition on tubing and connections. O'Riordan et al.recommends that nebulizer configuration be specified in treatmentprotocols.

Large Particle Aerosolization

In contrast to the references discussed above, Negley et al., ENTJournal, 78(8):550-554 (1999), et al., (presented at the ENT AcademyMeeting, May 1999) teach large particle nebulization therapy fortreatment of sinusitis. Negley observes that deposition of medicationinto the sinuses is best achieved when the aerosolized particles are 16to 25 μm in size. Desrosiers et al. reports that large particle salineaerosol therapy alone is effective in treating refractory sinusitis andthat the addition of tobramycin to the saline solution had minimalbenefit.

The journal articles and patents discussed above teach various aerosoltherapies for the treatment of sinusitis. However, there does not appearto be agreement among the various authors as to the optimal size or sizedistribution of the aerosolized particles or even whether antibioticsare effective in treating sinusitis. What has been needed is aclinically effective anti-infective treatment protocol for sinusitis, amore optimal therapy schedule, and an appropriate nebulizerconfiguration for the deposition of aerosolized anti-infective particlesinto the sinuses for the successful and consistent treatment of chronicsinusitis.

SUMMARY

Provided are pharmaceutical compositions that include one or more activeingredients such as anti-infective, anti-inflammatory and mucolyticagents. Such compositions preferably are formulated as a solution in aunit dose or multi-dose vial for aerosol administration to the nasalsinuses. It is contemplated that such formulations are packaged withlabels or inserts or other forms of directions for their use in thetreatment of sinusitis.

In a preferred embodiment, the surface tension of the solution isbetween about 10 to 70 dynes/cm, in order to yield an aerosol having apreferred Mass Median Aerodynamic Diameter within the range of about 1.0to 4.0 microns. The use of such an aerosolized spray has minimalsystemic side effects. Surface tension of a given formulation may beadjusted by adding a surfactant in addition to the active ingredients inorder to bring it into the preferred range.

Generally, it is contemplated that formulations according to the presentinvention will preferably have a pH in the range of about 3.0 to 8.5; anosmolality of the solution between about 150 mOsm/kg to 880 mOsm/kg; anda NaCl equivalency to the solution is preferably between about 0.9% NaClto 3.0% NaCl.

Preferred anti-infective agents include Penicillins, Cephalosporins,Macrolides, Sulfonamides, Quinolones, Aminoglycosides, BetaLactamantibiotics, Linezolid, Vancomycin, Amphotericin B, and Azoleantifungals. Preferred anti-inflammatory agents include Glucocorticoids,Disodium Cromoglycate and Nedcromil Sodium. Preferred mucolytic agentsare Acetylcysteine and Dornase Alpha. Preferred decongestant agents arePhenylephrine, Naphazoline, Oxymetazoline, Tetrahydrozoline andXylometoazoline.

Exemplary pharmaceutical compositions contain one or more activeingredients selected from the group consisting of anti-infective,anti-inflammatory and mucolytic agents, wherein the surface tension ofthe solution is between about 10 to 70 dynes/cm, said composition beingformulated as a solution in a unit dose for aerosol administration tothe nasal sinuses and being packaged with directions for its use in thetreatment of sinusitis. The pH of the composition typically ranges fromabout 3.0 to 8.5. The osmolality typically ranges from 300 mOsm/kg to880 mOsm/kg, where the NaCl equivalency to the solution is generallybetween about 0.9% NaCl to 3.0% NaCl. The compositions also contain asurfactant. The compositions can additionally contain other activeagents for treatment of sinusitis, such as a decongestant.

In one embodiment, the agent is an anti-infective agent and thesinusitis is caused by a pathogen selected from among Alpha Hemolyticstreptococci, Beta Hemolytic streptococci, Branhamella Catarrhalis,Diptheroids, Haemophilis influenzae (beta-lactamase positive andnegative), Moraxella species, Pseudomonas aeruginosa, Pseudomonasmaltophilia, Serratia marcescens, Staphylococcus aureus, Streptococcuspneumonia, Aspergillosis, Mucor and Candida Albicans, Fusarium,Curvularia, cryptococcus, coccidioides, and histoplasma. Theanti-infective agent can be selected from among Penicillins,Cephalosporins, Macrolides, Sulfonamides, Quinolones, Aminoglycosides,BetaLactam antibiotics, Linezolid, Vancomycin, Amphotericin B, and Azoleanfifungals. The surfactant can be a polysorbate, such as polysorbate 20to polysorbate 85.

The compositions can be formulated as an aerosol. In one embodiment, atleast about 85% of the aerosolized particles have a Mass MedianAerodynamic Diameter within the range of about 1.0 to 4.0 microns. Theseaerosols can be effective to kill at least about 90% of susceptiblesinusitis-causing pathogens present in the sinus passages of a sinusitispatient within about 14 days following an every 8 hr (TID), every 12 hr(BID), or every 24 hr (AD) administration protocol.

Kits containing the compositions are provided. In a one embodiment, akit is described that provides the various equipment and attachmentsuseful in administering the formulations of the present invention byusing the disclosed nebulizer devices. In one embodiment, the kitscontain a nebulizer cup with a nasal adapter for delivering thecomposition in aerosolized form to the nasal sinuses. This kit can becombined with a nebulizer device.

Methods of treatment a patient suspected or diagnosed as having chronicsinusitis are provided. Preferred administration protocols also aredescribed. The pharmaceutical composition, for example, can beadministered to the patient 1-3 times a day for a total of 14-21 days.These methods can include the step of administering to thepharmaceutical composition by aerosolization using a nebulizer, whichdelivers aerosol particles of between about 1 to 5 μm in averagediameter. Nebulizers that deliver aerosol particles between about 1 to 5μm in average diameter are known in the art (see U.S. Pat. No.5,508,269). One exemplary nebulizer is a PARI nebulizer with a nasaladapter. The nebulizer can be connected to a PARI SinuNEB compressorwhich is an exemplary device to generate an airflow to deliver thecomposition. The nebulizer can deliver a majority of aerosolizedparticles in the size range of about 3.0 to 3.5 μm in diameter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 discloses the preferred equipment for aerosolized delivery ofpharmaceutical solutions. This nebulizer, manufactured by PariRespiratory Equipment, Inc., for the inventors, produces the desiredparticle size for effective administration of the solutions in thisinvention to the sinuses. To use this nebulizer preferably medication isplaced in the nebulizer at A. The nebulizer is then connected to acompressor or other source at B with tubing supplied. When the airflowis turned on, the patient places the nose piece C under their nostrilsand breathes normally until the medication solution in the nebulizerbegins to sputter and no mist comes out at C.

DETAILED DESCRIPTION OF THE INVENTION I. General Description

The present invention involves the topical delivery of medications tothe nasal cavity and sinuses by aerosolizing aqueous solutions of thesemedications. The present invention is based in part on the surprisingfinding that aerosolized anti-infective particles are surprisinglyeffective therapeutically when they have a mass median aerodynamicdiameter (MMAD) of about 3.0 to 3.5 μm for deposition in the sinuses ina preferred size range. The present invention provides an apparatus fordelivery of such optimally sized anti-infective particles into thesinuses. The present invention is also based in part on the finding thatthe addition of a surfactant to formulations increases the deposition,retention, and penetration of anti-infectives or other activeingredients into the sinuses. The present invention provides guidancefor therapy schedule and dosage as discussed in detail below.

As described in greater detail below, the pharmaceutical formulationswill be aerosolized/atomized prior to administration to a patient toform an aerosol cloud with particles of aerosolized/atomized H₂O andmedication that have a MMAD (Mass Median Aerodynamic Diameter) ofpreferably between about 0.5 and 5.0 microns, more preferably betweenabout 1.0 to 4.0 microns and most preferably between about 2.0 to 3.5microns. It is also preferable to have the maximum number of particlesover 5.0 microns be less than 20% of the total particles.

A surprising discovery made by the inventors was that the surfacetension of the solution prepared for inhalation needed to be adjusted toachieve optimal results. To achieve effective deposition of medicationwithin the sinuses it is preferable to have the surface tension of thesolution for aerosolization be adjusted with surfactants to between 10dynes/cm and 70 dynes/cm, more preferably between about 20 to 60dynes/cm, and most preferably between about 30 to 50 dynes/cm.

Contemplated pharmaceutical compositions will include one or more activeingredients such as anti-infective, anti-inflammatory and mucolyticagents. Appropriate medications to be used in the methods according tothe present invention are listed in Table 1. These medications may beadministered for the treatment of sinusitis, particularly chronicsinusitis, by resolving infection, reducing inflammation or reducingcongestion in the nasal cavity and sinuses.

These compositions ideally will be formulated as a solution in a unitdose or multi-dose vial for aerosol administration to the nasal cavityand sinuses and packaged with directions for its use in the treatment ofsinusitis. Appropriate compositions for this purpose will be formulatedby using surfactants, NaCl or other chemicals entities to adjust thesolution for administration to have the following properties:

-   -   surface tension preferably between about 10 to 70 dynes/cm, more        preferably between about 20 to 60 dynes/cm, and most preferably        between about 30 to 50 dynes/cm.    -   osmolality between about 300 mOsm/kg to 880 mOsm/kg, more        preferably between about 400 mOsm/kg to 700 mOsm/kg and most        preferably between about 500 mOsm/kg to 600 mOsm/kg.    -   NaCl equivalency of the solution preferably between about 0.9%        NaCl and 3.0% NaCl, more preferably between about 1.1% NaCl and        1.8% NaCl and most preferably between about 1.3% NaCl and 1.7%        NaCl.    -   pH preferably between about 3.0 and 8.5, but may vary according        to the properties of the medication used.        A. Surface Tension

The present inventors have found that the surface tension and, to alesser degree, particle size are critical factors in getting optimaldeposition of the formulation in the nasal cavity and sinuses. Forexample, particles that are too large will deposit in the nasal cavity,but are unlikely to enter the sinuses. Having too low a surface tensionincreases an aerosolized particle's chance of deposition on the firstsurface that it comes in contact with, which generally would be tissueor structures in the nasal cavity proximal to the sinuses. In contrast,if the surface tension is too high, much of the aerosolized medicationis not deposited within the patient's sinuses and ultimately isdeposited in the lungs. If the surface tension is too low most of theaerosolized medication is deposited in the nasal cavity and does notreach the sinuses.

For purposes of preparing formulations according to the presentinvention, surface tension may be measured by using a Ring Tensiometeror the capillary rise measure method which consists of a capillary tubeof known diameter placed into the solution and a measurement ofcapillary rise taken to provide surface tension. Surface tension willthen be adjusted using surfactants to fall within a preferred range indynes/cm.

B. Osmotic Pressure

Optimal osmotic pressure helps to reduce damage to the epithelia ciliaof the sinuses. Although often not present in chronic sinusitispatients, epithelia cilia perform a useful function in the sinuses bymoving mucosal fluid out of the sinuses.

For purposes of preparing formulations according to the presentinvention, osmolality may be measured by using an Osmometer. Ifnecessary, osmolality may then be raised to fall within a preferredrange by adding NaCl to the solution.

C. Sodium Chloride Equivalency

Optimal NaCl equivalency (tonicity) works to reduce swelling in thesinuses and nasal cavity by drawing water from the nasal and sinusepithelia, reducing swelling. NaCl equivalency below 0.9% (hypotonic)may cause swelling in the epithelia of the nasal cavity and sinuses.NaCl equivalency above 3.0% would raise the tonicity and osmoticpressure above desirable levels and may cause a burning sensation.

For purposes of preparing formulations according to the presentinvention, NaCl equivalency will closely follow osmotic pressure and canbe measured using the methods described in section B above.

D. pH

In general, the pH would be adjusted if a given medication is eithermore stable or more effective at a certain pH. American HospitalFormulary Service (AFHS) published yearly or the Hand Book of InjectableDrugs by Lawrence A. Trissel,© 1994 American Society of HospitalPharmacists, Inc., which are herein incorporated by reference, provideinformation regarding the stability or effectiveness of a medication atcertain pH.

For the purposes of preparing formulations according to the presentinvention the pH of the various solutions may need to be adjusted toachieve stability or increase effectiveness. A pH meter, where a probeis placed into the solution and the device gives the pH, will be used tomeasure pH or pH paper will be used to estimate pH by placing solutionon the tape and then comparing to a predeveloped chart of pHcolorations. When necessary, pH will then be adjusted to arrive at themost preferable range of pH needed for nasal aerosolization by addingbuffering agents.

E. General Preparation of a Unit Dose and Production of Aerosol withOptimal Particle Diameter

After determining the medications to be used in the formulation, eachingredient is weighed/measured out individually, added together anddissolved in sterile water for injection. The preparation is then testedto ensure that it is within the parameters established for surfacetension, osmolality, pH, and sodium chloride equivalency. This is doneby using the appropriate equipment for each test as noted in Sections Ato D above. To prepare a unit dose, the ingredients of such formulationsgenerally will be dissolved in a solvent such as water or salinesolution, in a volume between about 0.5 and 6.0 mls, more preferablybetween about 2 and 4 mls and most preferably between about 2.5 and 3.5mls.

F. Surfactants

The surface tension of a fluid is the tendency of the fluid to “stick”to itself when there is a surface between the liquid and the vapor phase(known as an interface). A good example is a drop of water falling inair. The drop assumes a spherical shape due to surface tension forces,which minimize its surface given the volume. Molecules at the surface ofa liquid exert strong attractive forces on other molecules within theirvicinity. The resultant force acting perpendicular to a line of unitlength in the surface is known as surface tension, usually measured inDynes/Centimeter.

Surfactants can be used as dispersing agents, solubilizing agents andspreading agents. Some examples of surfactants are: Polyethylene glycol400; Sodium lauryl sulfate; sorbitan laurate, sorbitan palmitate,sorbitan stearate (available under the name SPAN® 20-40-60 etc.);polysorbates including, but not limited to, polyoxyethylene (20)sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate,polyoxyethylene (20) sorbitan monostearate (available under thetradename TWEEN® 20-40-60 etc.); and Benzalkonium chloride. The purposeof using surfactants in the preferred formulations of the presentinvention is to adjust the surface tension of the aerosolized particlesso that the maximum amount of medication is deposited in or near themiddle meatus ostea. If the surface tension is reduced too much, themajority of the particles will deposit in the nasal cavity, converselyif the surface tension is too high the particles go directly to thelungs without depositing in the nasal sinuses.

The HLB (hydrophile-lipophile-balance) is used to describe thecharacteristics of a surfactant. The system consists of an arbitraryscale to which HLB values are experimentally determined and assigned. Ifthe HLB value is low, the number of hydrophilic groups on the surfactantis small, which means it is more lipophilic (oil soluble).

Surfactants can act as solubilizing agents by forming micelles. Forexample, a surfactant with a high HLB would be used to increase thesolubility of an oil in an aqueous medium. The lipophilic portion of thesurfactant would entrap the oil in the lipophilic (interior) portion ofthe micelle. The hydrophilic portion of the surfactant surrounding ofoil globule would, in turn, be exposed to the aqueous phase.

An HLB value of 10 or higher means that the agent is primarilyhydrophilic, while an HLB value of less than 10 means it would belipophilic. For example, SPAN®s have HLB values ranging from 1.8 to 8.6,which is indicative of oil soluble for oil dispersible molecules.Consequently, the oil phase will predominate and a water/oil emulsionwill be formed. TWEEN®s have HLB values that range from 9.6 to 16.7,which is characteristic of water-soluble or water dispersible molecules.Therefore, the water phase will predominate and oil/water emulsions willbe formed.

Emulsifying agents are surfactants that reduce the interfacial tensionbetween oil and water, thereby minimizing the surface energy through theformation of globules. Wetting agents, on the other hand, aid inattaining intimate contact between solid particles and liquids.

Detergents are also surfactants that reduce the surface tension and wetthe surface as well as the dirt. When a detergent is used, the dirt willbe emulsified, foaming may occur and the dirt will then wash away.

G. Pathogens Known to Produce Acute and Chronic Sinus Infections

A retrospective review of sinus cultures obtained over a 4-year periodfrom a consecutive series of patients who underwent endoscopic sinussurgery (ESS) was conducted by Niel Bhattacharyya M. D. et al.; Archivesof Otolaryngology-Head and Neck surgery Vol. 125 No. 10, October 1999. Awide range of bacteria may be present in the infected post-ESS sinuscavity, with a considerable population of gram-negative organisms,including Pseudomonas species. Fungal infections of the sinuses have anonspecific clinical presentation, is refractory to standard medicaltreatment and may produce expansion and erosion of the sinus wall.Various factors have been implicated in the development of fungalsinusitis: anatomical factors in the osteomeatal complex, tissularhypoxia, traumatic factors, massive exposure to fungal spores, allergyand immunosuppression.

The most common bacterial organisms found are the following: AlphaHemolytic streptococci, Beta Hemolytic streptococci, BranhamellaCatarrhalis, Diptheroids, Haemophilis influenzae (beta-lactamasepositive and negative), Moraxella species, Pseudomonas aeruginosa,Pseudomonas maltophilia, Serratia marcescens, Staphylococcus aureus andStreptococcus pneumonia.

The most common fungal organisms found are the following: Aspergillosis,Mucor and Candida Albicans, Fusarium, Curvularia, cryptococcus,coccidioides, and histoplasma.

The optimum treatment modality is for the physician to obtain a culturefrom the sinus cavities via endoscope. The culture is sent to alaboratory where it is tested for minimum inhibitory concentration forseveral antibiotics and then the correct antibiotic can be chosen basedon the sensitivities provided by the laboratory. Current therapy by mostOtolaryngologists is to determine the best antibiotic by using theirclinical experience in treating sinus infections. This is called empirictherapy.

The anti-fungal therapy is done similarly in that it can also becultured and sent to the lab for identification allowing the mosteffective agent to be prescribed, or empiric therapy is performed by thephysician.

The kill rate is determined by the susceptibility of the organism to theantibiotic or antifungals. If culture and sensitivities are performedand the correct antibiotic is prescribed the kill rate occurs between aperiod of one to three weeks. The kill is determined/measured by arepeat culture and sensitivity test showing no bacterial or fungalgrowth (as appropriate).

II. Specific Embodiments

A. Pharmaceutical Compositions and Formulations

Preferred anti-infective agents include Penicillins, Cephalosporins,Macrolides, Sulfonamides, Quinolones, Aminoglycosides, BetaLactamantibiotics, Linezolid, Vancomycin, Arnphotericin B, and Azoleantifungals. Preferred anti-inflammatory agents include Glucocorticoids,Disodium Cromoglycate and Nedcromil Sodium. Preferred mucolytic agentsare Acetylcysteine and Dornase Alpha. Preferred decongestant agents arePhenylephrine, Naphazoline, Oxymetazoline, Tetrahydrozoline andXylometoazoline. These agents may be found in the American HospitalFormulary Service published by American Society of Hospital Pharmacists,Inc., which is incorporated herein by reference.

As an example of a contemplated formulation, Cefuroxime is formulated indosages of 285 mg in 3 ml sterile water for injection per dose, toproduce an antibiotic for aerosol administration. This formulation maybe compounded under a Laminar Flow hood by performing the followingsteps: 1) weigh out sufficient cefuroxime to provide 21 doses of 285 mgeach (5985 mg), with 5% overage to account for that lost in compounding;2) QS ad (add up to) to 63 ml with sterile water, with 5% overfill forloss in compounding; and 3) adding 0.1 ml of polysorbate 20 per 100 mlsolution.

The formulation is tested using a Ring Tensiometer or the Capillary Risetest to determine the surface tension of the solution. The preferablerange is 10 to 70 dynes/cm. The formulation may be adjusted with asurfactant if necessary using, for example, polysorbate 20. Using a pHmeter, the formulation is tested for the desirable pH, preferably in therange of about 3.0 to 8.5. The pH is adjusted with appropriate acids,bases and appropriate buffers as needed according to conventionalcompounding practices.

Preferably the formulation will also be evaluated using E tables fromsources known to practitioners skilled in the pharmaceutical arts, suchas Remington: The Science and Practice of Pharmacy or other suitablepharmaceutical text to calculate its sodium chloride equivalence toensure that it is in the preferred range of 0.9% to 3.0%. Similarly, theosmolality is checked to ensure that it falls within the preferred rangeof about 300 to 880 mosmikg. If osmolality falls outside of this range,the polysorbate 20 component may be decreased until the preferredconditions are met.

As a second example, Ciprofloxacin is formulated in dosages of 90 mgunit dose in 3 ml of sterile water for injection per dose. Becausecompounds of this antibiotic class (i.e., Fluoroquinolones) do not haveinherent surfactant activities, a surfactant preferably is added tolower the surface tension of the final product.

This formulation may be compounded under a Laminar Flow hood byperforming the following steps: 1) weighing out a sufficient quantity ofCiprofloxacin powder to prepare 28 doses (2520 mg) with 5% overage toaccount for loss during compounding; 2) QS ad to 74 ml sterile water forinjection (add 5% overage for loss in compounding); and 3) adding 0.25ml polysorbate 20 for every 100 ml of solution.

The formulation is tested as described above and adjustments made tobring surface tension, pH, sodium chloride equivalence and osmolalitywithin preferred ranges or to preferred levels.

As a third example, Amphotericin B is formulated in 10 mg unit dosesalong with Hydrocortisone sodium succinate in 50 mg unit doses in 3 mlsterile water to provide an antifungal agent together with ananti-inflammatory agent.

This formulation may be compounded under a Laminar Flow hood byperforming the following steps: 1) weighing out sufficient powder ofAmphotericin B to make 28 doses (280 mg) of 10 mg each allowing 5%overage for loss in compounding; 2) weighing out sufficient powder ofHydrocortisone sodium succinate to make 28 doses (1400 mg) of 50 mg eachallowing 5% overage for loss of compounding; 3) combining powders; and4) QS ad sterile water for injection to 84 ml plus 5% for loss incompounding. The formulation is tested as described above andadjustments made to bring surface tension, pH, sodium chlorideequivalence and osmolality within preferred ranges or to preferredlevels.

As a fourth example, Ofloxacin is formulated in 90 mg unit doses alongwith Acetylcystiene in 100 mg unit doses in 3 ml of sterile water toprovide an antibiotic together with a mucolytic agent for injection.

This formulation is compounded under a Laminar Flow Hood by performingthe following steps: 1) weighing out sufficient powder of Ofloxacin tomake 28 doses (2520 mg) of 90 mg each allowing 5% overage for loss incompounding; 2) weighing out sufficient powder of Acetylcysteine to make28 doses (2800 mg) of 100 mg each allowing 5% overage for loss incompounding; and 3) combining the powders and QS ad to 84 ml withsterile water for injection allowing 5% overage for loss duringcompounding. The formulation is tested as described above andadjustments made to bring surface tension, pH, sodium chlorideequivalence and osmolarity within preferred ranges or to preferredlevels.

As a fifth example, Tobramycin is formulated in 100 mg unit doses in 2.5ml of saline solution to provide an alternative antibiotic formulation.The formulation is compounded under a Laminar Flow hood by performingthe following steps: 1) weighing out the tobramycin powder sufficient toprovide 42 doses of 100 mg per dose (4200 mg), allowing for 5% overagedue to losses during compounding; 2) QS ad with 105 ml of sterile waterfor injection, allowing for 5% overage due to losses during compounding;and 3) adding 0.15 ml polysorbate 20 to adjust surface tension. Theformulation is tested as described above and adjustments made to bringsurface tension, pH, sodium chloride equivalence and osmolality withinpreferred ranges or to preferred levels.

As a sixth example, Cefoperazone and Oxymetazoline are formulated in 3ml of Sterile water for injection to provide an antibiotic formulatedwith a decongestant. This formulation is prepared under a Laminar FlowHood by following these steps: 1) weighing out sufficient powder ofCefoperazone to make 28 doses of 600 mg each (16.8 gm) allowing 5%overage for compounding loss; 2) weighing out sufficient powder ofOxymetazonline to make 28 doses of 0.5 mg each (14 mg) allowing 5%overage for compounding loss; 3) combining the powders together; 4) QSad with sterile water to 84 ml allowing 5% overage for compounding loss;5) adding Benzalkonium Chloride 0.02% (0.02 gm/100 ml of solution). Theformulation is tested as described above and adjustments made to bringsurface tension, pH, sodium chloride equivalence and osmolality withinpreferred ranges or to preferred levels.

B. Determination of the Course of Treatment

In general, the course of treatment for any given patient will bedetermined by his or her physician. Thus, if the organisms found in apatient's sinuses are cultured by known techniques and theirsensitivities are determined, the most appropriate antibiotic will beordered. However, if no cultures and sensitivities are done, then thepatient also may be treated empirically with the antibiotic chosen bythe physician using his or her experience based on what bacteria orfungus is suspected. If the anatomical structures inside the nasalpassageways are swollen or inflamed due to allergy or flu symptoms, ananti-inflammatory agent or a decongestant agent also may be administeredif the patient is not otherwise using nasal sprays or oral medicationseparately.

Example of a Patient Treatment Scenario

1. Patient contracts what they feel is a sinus infection and goes totheir Otolaryngologist for diagnosis. After determining the diagnosis ofsinusitis, a culture is obtained endoscopically and sent to thelaboratory.

2. The laboratory determines the bacteria/fungus sensitivities by drugand reports its findings to the physician.

3. The physician faxes the report to the pharmacy along with aprescription for the antibiotic most appropriate for the infection. Theformulation is prepared as described above and dispensed in 2.5 mlcontainers. Generally, the container will be labeled: “Store inRefrigerator.”

4. The physician will call patient and discuss the treatment and anypertinent data necessary to enhance the treatment outcome.

C. Contemplated and Preferred Treatment Regimens

The preferred treatment is the antibiotic (adjusted for the propersurface tension, pH, sodium chloride equivalence, and osmolality) thatmost effectively kills the bacteria or fungus as determined by cultureand sensitivity, administered once to three times per day for a durationof 5 to 10 minutes per each treatment (See Table 1).

The total number of days needed to rid the infection preferably isdetermined by reculturing until no growth is noted. However, when thephysician does not do culturing, the conventional standard of practiceis two weeks of therapy until patient generally would be expected tohave become asymptomatic plus an additional 7 days of therapy.

D. Monitoring Efficacy

The typical Otolaryngologist when treating chronic sinusitis prescribesantibiotics until the patient is symptom free by physical exam plus anadditional seven days. The problem that occurs with respect to sinusinfections is that, if the infection is not completely resolved, thepatient will have a recurrence the next time their immune system ischallenged, i.e., they contract the flu, go through a stressful time intheir life or need chemotherapy treatments. Thus, the preferred methodof determining resolution of the infection is to reculture the sinusesendoscopically and have the laboratory report come back negative, i.e.,reporting no growth of pathogenic microorganisms. The present inventorshave discovered that aerosolization should lead to less resistanceexhibited by bacteria due to the fewer times they are exposed to theantibiotic, and such exposure occurs at lower dosages and for shorterperiods of time of aerosolized administration (typically 1-3 weeks) ascompared to oral (typically 3 weeks to several months) and intravenoustreatment (typically 3-6 weeks).

E. Equipment for Aerosolized Delivery of Pharmaceutical Composition

Equipment for aerosolized delivery of pharmaceutical compositions arewell known to the skilled artisan. O'Riordan et al., Journal of AerosolMedicine, 20(I):13-23 (1997), reports the delivery of aerosolizedtobramycin by a jet nebulizer and an ultrasonic nebulizer. U.S. Pat. No.5,508,269, issued April 16, 1996, compares the characteristics of threedifferent nebulizers: the Ultraneb 99 (DeVilbiss) ultrasonic nebulizer,the Medicaid Sidestream jet nebulizer, and the Pari LC jet nebulizer.

The preferred equipment for aerosolized delivery of pharmaceuticalsolutions is depicted in FIG. 1. This nebulizer manufactured by PariRespiratory Equipment, Inc. for the inventors produces the desiredparticle size for effective administration of the solutions in thisinvention to the sinuses. To use this nebulizer preferably 1 ml to 5 mlof medication solution, more preferably 2 ml to 4 ml and most preferably2.5 ml to 3.5 ml of medication solution is placed in the nebulizer at A.The nebulizer is then connected to a compressor or other source of 4liter/minute airflow at B with tubing supplied. When the airflow isturned on the patient places the nose piece C under their nostrils andbreathes normally until the medication solution in the nebulizer beginsto sputter and no mist comes out at C. This will usually take 8 to 10minutes.

In light of the foregoing general discussion, the specific examplespresented below are illustrative only and are not intended to limit thescope of the invention. Other generic and specific configurations willbe apparent to those persons skilled in the art.

EXAMPLES Example 1 Patient A

A female in her forties had been suffering from sinusitis for most ofher adult life. These sinusitis episodes seemed to be triggered byallergies. She historically had three-four (3-4) episodes of sinusitiseach year, which were treated with oral antibiotics for four-eight (4-8)weeks per episode. These oral antibiotic regimens produced yeastinfections, which were treated with Diflucan® (fluconazole). Relief fromthe headaches, malaise, facial pressure and pain, yellow-green nasaldischarge, coughing and fever took up to six weeks and were treated withnarcotic and non narcotic analgesics, decongestants, decongestant nasalsprays, cough suppressants, and nasal rinses. Her allergies were treatedwith antihistamines and anti-inflammatory agents.

In an effort to reduce the duration of her sinusitis episodes, a nosedrop of tobramycin 80 mg/ml was administered. This treatment did notseem to work. The medication was irritating; and in order to administerthe drops and try to get them into the sinus cavity, the patient had tohold her head back. This caused intolerable pain resulting in thediscontinuation of the therapy. A nose drop of Bactoban® (Mupirocincalcium 2%) was tried. It was not efficacious; it was very viscous. Theadministration of this drop produced similar pain on administration, andthis therapy was also discontinued.

In order to eliminate the pain caused by holding her head back whenadministering nose drops, a nose drop of tobramycin was administeredafter the patient had been on oral antibiotics for a period of time.This did not seem to work. The drop did not seem to penetrate into thesinus cavities.

Thereafter, a preparation of tobramycin 80 mg/ml was administered using3 ml in a Pari LC Star® nebulizer cup with adult mask attached and aPari Proneb® compressor. The medication was nebulized three (3) timesdaily. After four days of therapy, the patient experienced a “dumping”of green, purulent nasal discharge. The therapy was continued for atotal of seven (7) days. It seemed at this point that the sinusinfection had been eliminated, but a relapse was experienced within amonth. Another seven (7) day regimen of nebulized tobramycin was givento the patient. Again the sinus infection seemed to be eliminated, butit reoccurred within two (2) months.

A preparation of cefuroxime 285 mg in 2.5 ml sterile water for injectionwas administered three (3) times daily using a Pari LC Star® nebulizercup with adult mask attached and a Pari Proneb® compressor. The time ofnebulization was extensive and the medication did not seem to becompletely nebulized. After one day of therapy, a Pari Turbo® compressorwas substituted for the Pari Proneb® compressor. The patient experienceda “dumping” of green, purulent nasal discharge after (3) days oftherapy. The therapy was continued for a total of seven (7) days, againshe contracted a yeast infection and was given Diflucan®.

After the seven (7) days of treatment with nebulized cefuroxime usingthe Pari Turbo® compressor and the Pari LC Star® nebulizer cup withmask, the patient has remained free of sinus infections for nine (9)months. She has continued to experience problems with her allergies, andwhile in the past these allergies triggered sinus infections, this timeno such infection has recurred.

Example 2 Patient B

A male in his forties had been experiencing sinus infections off and onduring his adult life. He was treated with cefuroxime 285 mg in 2.5 mlof sterile water for injection three (3) times daily using a Pari LCStar® nebulizer cup with adult mask attached and a Pari Turbo®compressor. The patient experienced a “dumping” of green, purulent nasaldischarge after eight (8) treatments. The therapy was continued for atotal of seven (7) days. No other antibiotics were given. This patienthas been free from sinus infections for six (6) months.

Example 3 Patient C

A female aged mid-50s had been suffering from sinusitis off and on formost of her adult life. These sinusitis episodes seemed to be triggeredby allergies. The patient took antihistamines and decongestants whenallergies triggered headaches and/or a clear nasal discharge.Historically, she would have one or more sinus infections a yearrequiring twenty or more days of oral antibiotics.

She was treated with cefuroxime 285 mg in 2.5 ml of sterile water forinjection three (3) times daily using a Pari LC Star® nebulizer cup withadult mask attached and a Pari Turbo® compressor. The patientexperienced a “dumping” of green, purulent nasal discharge after eight(8) treatments. The therapy was continued form a total of seven (7)days. No other antibiotics were given. This patient has been free fromsinus infections for six (6) months.

It should be understood that the foregoing discussion and examplesmerely present a detailed description of certain preferred embodiments.It therefore should be apparent to those of ordinary skill in the artthat various modifications and equivalents can be made without departingfrom the spirit and scope of the invention. All journal articles, otherreferences, patents and patent applications that are identified in thispatent application are incorporated by reference in their entirety.TABLE 1 Agents and Dosages More Most Most Preferable PreferablePreferable Preferable Generic Name Brand Name Class Range Range RangeDose Amikacin Amikin Aminoglycoside 50-500 mg 75-300 mg 100-200 mg 166mg Q8-12H Amphotericin B Fungizone Antifungal 2.5-45 mg 4-30 mg 7.5-15mg 10 mg Q12H Azithromycin Zithromax Macrolide 50-400 mg 75-300 mg150-200 mg 167 mg Q12H Aztreonam Azactam Monobactam 250-1000 mg 300-900mg 475-750 mg 450 mg Q8H Cefazolin Ancef, Kefzol Cephlasporin 250-1000mg 300-900 mg 575-700 mg 650 mg Q8H (Gen I) Cefepime MaxipimeCephlasporin 125-1000 mg 200-900 mg 575-700 mg 650 mg Q12H (Gen IV)Cefonicid Moniacid Cephlasporin 250-1000 mg 300-900 mg 575-700 mg 600 mgQ24H (Gen II) Cefoperazone Cefobid Cephlasporin 250-1000 mg 300-900 mg575-700 mg 600 mg Q12H (Gen III) Cefotaxime Claforan Cephlasporin250-1000 mg 300-900 mg 575-700 mg 600 mg Q8-12H (Gen III) CefotetanCefotan Cephlasporin 250-1000 mg 300-900 mg 575-700 mg 600 mg Q8-12H(Cephamycin) Cefoxitin Mefoxin Cephlasporin 250-1000 mg 300-900 mg575-700 mg 600 mg Q12H (Cephamycin) Ceftazidime Fortaz, Cephlasporin250-1000 mg 300-900 mg 475-750 mg 550 mg Q12H Ceptaz (Gen III)Ceftizoxime Cefizox Cephlasporin 250-1000 mg 300-900 mg 575-700 mg 600mg Q8-12H (Gen III) Ceftriaxone Rocephin Cephlasporin 250-1000 mg300-900 mg 575-700 mg 650 mg Q12H (Gen III) Cefuroxime CeftinCephlasporin 100-600 mg 200-520 mg 250-400 mg 285 mg Q8H (Gen II)Cephapirin Cefadyl Cephlasporin 250-1000 mg 300-900 mg 575-700 mg 650 mgQ12H (Gen I) Ciprofloxacin Cipro Quinolone 25-200 mg 50-175 mg 75-110 mg90 mg Q12H Clindamycin Cleocin Lincosamide 50-600 mg 75-500 mg 125-300mg 225 mg Q12H Doxycycline Vibramycin Tetracycline 10-100 mg 15-80 mg25-65 mg 27 mg Q12H Fluconazole Diflucan Antifungal 12.5-150 mg 20-70 mg25-50 mg 30 mg Q12H Gentamycin Garamycin Aminoglycoside 10-200 mg 30-150mg 80-120 mg 95 mg Q8-12H Itraconazole Sporanox Antifungal 12.5-150 mg20-70 mg 25-50 mg 30 mg Q12H Levofloxacin Levaquin Quinolone 40-200 mg50-150 mg 60-80 mg 70 mg Q12H Meropenem Merrin Carbapenem 200-750 mg250-700 mg 300-500 mg 333 mg Q8H Mezlocillin Mezlin Penicillin 300-1500mg 375-1000 mg 750-950 mg 833 mg Q6H Miconazole Monistat Antifungal12.5-300 mg 30-200 mg 50-100 mg 60 mg Q12H Nafcilin Nafcil Penicillin100-1000 mg 125-750 mg 250-600 mg 460 mg Q6H Ofloxacin Floxin Quinolone25-200 mg 50-175 mg 75-110 mg 90 mg Q12H Piperacillin PipracilPenicillin 100-1000 mg 125-750 mg 250-600 mg 460 mg Q6H Rifampin RafadinMiscellaneous 500-5000 mg 1000-4000 mg 1500-3500 mg 2250 mg Q12HTicarcillin + Clavulanate Timentin Penicillin 500-5000 mg 1000-4000 mg1500-3500 mg 2250 mg Q6-8H Tobramycin Nebcin Aminoglycoside 10-200 mg30-150 mg 80-120 mg 95 mg Q8-12H Vancomycin Vancocin Antifungal 50-400mg 75-325 mg 125-250 mg 166 mg Q6-8H

1. An aerosolized pharmaceutical composition, comprising: aerosolizedparticles of the composition, which contains an anti-inflammatory fortreating chronic sinusitis, and a surfactant, wherein: the aerosolizedcomposition is formulated for nasal administration as an aqueouscomposition; the aerosolized composition as formulated comprises fromabout 0.01% (w/v) to 0.03% (w/v) surfactant; the aerosolized compositionas formulated has a surface tension of about 10 to about 70 dynes/cm,wherein the surface tension is effective for retention, deposition andpenetration of the composition in the nasal sinuses; and wherein atleast about 80% of the aerosolized particles of the pharmaceuticalcomposition have a mass median aerodynamic diameter (MMAD) in the sizerange of about 0.5 μm to about 5.0 μm in diameter, whereby theaerosolized pharmaceutical composition is effective for treatment ofchronic sinusitis.
 2. The composition of claim 1, wherein thecomposition has a surface tension of about 30 to about 50 dynes/cm 3.The composition of claim 1, wherein the anti-inflammatory agentcomprises a glucocorticoid, disodium cromoglycate, nedcromil sodium or acombination thereof.
 4. The compositions of clam 3, wherein theanti-inflammatory agent is a glucocorticoid.
 5. The composition of claim1, wherein the composition is formulated for administration via anebulizer.
 6. The composition of claim 1, wherein at least about 80% ofthe particles have a mass median aerodynamic diameter (MMAD) in the sizerange of about 1.0 μm to about 4.0 μm in diameter.
 7. The composition ofclaim 1, wherein at least about 80% of the particles have a mass medianaerodynamic diameter (MMAD) in the size range of about 2.0 μm to about3.5 μm in diameter.
 8. The composition of claim 1, wherein less thanabout 20% of the total particles have a mass median aerodynamic diameter(MMAD) of greater than 5 μm.
 9. The composition of claim 1, wherein thecomposition has an osmolality of about 150 mOsm/kg to about 880 mOsm/kg.10. The composition of claim 1, wherein the composition has anosmolality of about 400 mOsm/kg to about 700 mOsm/kg.
 11. Thecomposition of claim 1, wherein the composition has an osmolality ofabout 500 mOsm/kg to about 600 mOsm/kg.
 12. The composition of claim 1,wherein the composition has a NaCl equivalency of about 0.9% to about3.0% NaCl.
 13. The composition of claim 1, wherein the composition has aNaCl equivalency of about 1.1% NaCl to about 1.8% NaCl.
 14. Thecomposition of claim 1, wherein the composition has a NaCl equivalencyof about 1.3% NaCl to about 1.7% NaCl.
 15. The composition of claim 1,wherein the composition has a pH of about 3.0 to about 8.5.
 16. Thecomposition of claim 1, wherein the composition comprises from about0.015% (w/v) to 0.025% (w/v) surfactant.
 17. The composition of claim 1,wherein the composition comprises about 0.02% (w/v) surfactant.
 18. Thecomposition of claim 1, wherein the surfactant comprises polyethyleneglycol 400, sodium lauryl sulfate, sorbitan esters, polysorbates,benzalkonium chloride or a combination thereof.
 19. The composition ofclaim 18, wherein the surfactant comprises polysorbate.
 20. Thecomposition of claim 1, wherein the surfactant has ahydrophile-lipophile-balance (HLB) of between about 1.8 to about 8.6.21. The composition of claim 1, wherein the surfactant has ahydrophile-lipophile-balance (HLB) of between about 9.6 to about 16.7.22. The composition of claim 1, wherein the composition is formulatedfor single dosage administration.